Age-related macular degeneration (AMD) and its neovascular complications cause permanent loss of central vision and legal blindness. There is currently no cure for macular degeneration. Treatment for AMD and its neovascular complications has been hampered by a lack of relevant animal models. Recently, however, at least half a dozen mutations in the Tissue Inhibitor of Metalloproteinases-3-encoding gene (TIMP-3) were identified in patients with Sorsby's fundus dystrophy (SFD) (1-3), a disease with similarities to neovascular AMD (4). Mice transgenic for one of these mutations, Y172C, were generated and found to possess retinal pathology culminating in retinal degeneration and subretinal neovascularization, as found in SFD. These TIMP-3/172 mice will provide insights into the pathogenesis of and a means to test potential treatments for macular degeneration. This proposal aims to delineate pathogenic mechanisms accounting for disease in the TIMP-3/172 mice and their human counterparts. Characterization of the pathogenic basis of this disease could suggest therapeutic approaches for treating SFD and other forms of macular degeneration. The project will have 3 components: The first will be to evaluate the effects of the TIMP-3/172 mutation on TIMP-3 function and on angiogenesis. The second will be to identify genetic variables that modify disease progression in the mutant TIMP-3 transgenic mice. Finally, patterns of gene expression in diseased retinal cells in the TIMP-3 transgenic mice will be evaluated and compared with those in unaffected cells. These studies aim to reveal specific biological pathways relevant to the pathology in this animal model. Any such pathways could potentially be manipulated in the future to slow/prevent the disease process.